Receptor activator of the NFκB ligand system protects renal function during experimental renal ischemia-reperfusion in mice

2020 ◽  
Vol 58 ◽  
pp. 101263
Author(s):  
Yuki Nakayama ◽  
Naohito Isoyama ◽  
Takeshi Yamamoto ◽  
Yudai Nagata ◽  
Masafumi Matsumura ◽  
...  
Keyword(s):  
Renal Function ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Ligand System ◽  
Receptor Activator

MO336RENAL CONTRAST-ENHANCED ULTRASOUND (CEUS) TO EVALUATE EARLY AND CHRONIC MODIFICATIONS OF RENAL PERFUSION AND TO PREDICT RENAL DYSFUNCTION AFTER RENAL ISCHEMIA-REPERFUSION IN MICE

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Maxime Schleef ◽  
Delphine Baetz ◽  
Christelle Leon ◽  
Bruno Pillot ◽  
Gabriel Bidaux ◽  
...  
Keyword(s):  
Renal Function ◽  
Ischemia Reperfusion ◽  
Renal Perfusion ◽  
Renal Ischemia ◽  
Renal Ultrasound ◽  
Mechanical Index ◽  
Contrast Enhanced Ultrasound ◽  
Serum Urea ◽  
Non Invasive ◽  
Contrast Enhanced

Abstract Background and Aims Renal ischemia-reperfusion can lead to acute kidney injury (AKI), increasing the risk of developing chronic kidney disease (CKD) through inflammation and vascular lesions. Serum urea or creatinine level routinely used as diagnostic indices of renal function are always delayed from the onset of the disease. Therefore, we currently lack reliable markers to early detect AKI, especially in animals. We aimed to show that non-invasive renal contrast-enhanced ultrasound (CEUS) could be a reliable tool to assess early and chronic changes of renal perfusion after renal ischemia-reperfusion. Method Male C57BL6 mice underwent 15 minutes of unilateral renal ischemia by clamping of the left renal vascular pedicle (n = 7), or a sham procedure (n = 3), under inhaled general anesthesia by Sevoflurane. A renal ultrasound was performed on the left ischemic kidney at baseline 1 week before the surgery, then, 20 minutes after reperfusion to assess early modifications of renal perfusion, and 1 month after reperfusion to follow chronic modifications. CEUS was performed in supine position by using a high-resolution ultrasonic imaging system (VEVO 3100 Fujifilm Visualsonics, Toronto, Canada) with a MX550D probe fixed in place with an iron support, ensuring the constant imaging plane throughout acquisition. First, a continuous infusion of microbubbles (VS-11913, Fujifilm Visualsonics, Toronto, Canada) was done through the tail vein, then a high mechanical index burst was given to destroy microbubbles when the contrast enhancement had reached a steady state, and finally, low mechanical-index imaging mode was used until, and 30 sec after the contrast agent concentration reached the plateau. Images were recorded and were analyzed using the “destruction-replenishment” fitting model of the Vevo LAB software (Fujifilm Visualsonics, Toronto, Canada). Renal perfusion was estimated by the total renal Blood Volume (rBV) parameter and was expressed as percentage of the baseline value for each animal. Renal function was also assessed by serum urea concentration 1 month after reperfusion, and the long axis lengths of both the kidneys were measured ex vivo after the mice were euthanized. Results Renal perfusion of the ischemic kidney measured by CEUS was significantly decreased as soon as 20 minutes of reperfusion compared to baseline (median 28,8% of baseline value; interquartiles [20,1 – 69,8%]). 1 month after reperfusion, renal perfusion recovered partially but was still significantly decreased compared to baseline (median 79,9% of baseline value; interquartiles [52,8 – 99,9%]) (Figure A). In sham operated mice, renal perfusion did not differ from baseline at 20 minutes or 1 month (p > 0.05). The renal function, assessed by serum urea, was mildly but significantly impaired 1 month after ischemia-reperfusion compared with sham (median serum urea 9,8 vs. 7,6 mmol/L) (p = 0.02), and this was consistent with the observed kidney atrophy in the ischemic group when compared to the contralateral kidney (median long axis length 7,5 vs 10,8 mm) (p = 0.03). Moreover, the decrease of renal perfusion 20 minutes after reperfusion was significantly correlated with the impairment of renal perfusion 1 month after reperfusion (Pearson r = 0.836, p = 0.005) and with the serum urea level at 1 month (Pearson r = -0.710, p = 0.03) (Figure B-C). Conclusion Renal CEUS was able to detect early impairment of renal perfusion as soon as 20 minutes after 15 minutes of renal ischemia in mice, and perfusion was still decreased 1 month after reperfusion, compared to baseline. This early impairment of perfusion was correlated with the chronic decrease of renal perfusion and renal function 1 month after reperfusion. This was also associated with a significant kidney atrophy. CEUS is an interesting non-invasive tool to assess renal lesions dynamically after ischemia-reperfusion.

scholarly journals P0536HYPOTHERMIA DURING RENAL ISCHEMIA-REPERFUSION IN MICE: A PROTECTIVE EFFECT ON RENAL AND MITOCHONDRIAL FUNCTIONS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Maxime Schleef ◽  
Delphine Baetz ◽  
Bruno Pillot ◽  
Christelle Leon ◽  
Noelle Gallo-Bona ◽  
...  
Keyword(s):  
Renal Function ◽  
Complex I ◽  
Mild Hypothermia ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Serum Urea ◽  
Mitochondrial Stress ◽  
Urea Level ◽  
Mitochondrial Functions ◽  
Significant Difference

Abstract Background and Aims Renal ischemia reperfusion (RIR) can induce mitochondrial stress triggering cell death and eventually leading to acute kidney injury (AKI). It has been suggested that mild hypothermia could be protective in RIR without clear underlying mechanisms. We aimed to show that mild hypothermia (34°C) during RIR protects renal mitochondrial function and prevents AKI. Method Male C57BL6 mice were assigned to 4 groups: normothermic ischemic (RIR-37°C) group (n=14) and hypothermic ischemic (RIR-34°C) group (n=14) with body temperature maintained at respectively 37°C or 34°C during 20 minutes of renal ischemia by bilateral renal clamping under general anesthesia; normothermic sham (Sham-37°C) group (n=10) and hypothermic sham (Sham-34°C) group (n=10) with only anesthesia and laparotomy at 37°C or 34°C respectively. Renal function (serum urea concentration) and isolated renal mitochondria function (capacity of mitochondria to retain calcium i.e. calcic retention capacity (CRC), and oxidative phosphorylation capacity of electron transport chain complexes (complex I, II and IV)) were assessed 2 hours and 24 hours after reperfusion. All animal procedures were approved by local Ethics Committee. Data are presented as median with IQR. Results All the parameters monitored were not modified by the temperature in the sham groups, and there was no mortality in those 2 groups. Mortality was 33% in the RIR-37°C group and 11% in the RIR-34°C group 24 hours after reperfusion (p=0.58). Renal ischemia was responsible for a significant increase of serum urea level 2 hours after reperfusion at 37°C [18.7 (17.3–19.0) mmol/L] compared to sham groups (p=0.02), whereas no significant increase was observed in the RIR-34°C group. After 24 hours of reperfusion serum urea level was improved in the RIR-34°C group [22.7 (11.5–42.0) mmol/L] compared to RIR-37°C [60.8 (58.0–69.7) mmol/L, p=0.001]. CRC was not modified by RIR after 2 hours of reperfusion in both groups. CRC was preserved 24 hours after reperfusion in the RIR-34°C group [260 (210–320) nmol Ca2+/mg protein] with no difference compared to Sham-37°C [320 (280–360) nmol Ca2+/mg protein p=0.18] whereas CRC was significantly decreased in the RIR-37°C group compared to Sham-37°C [120 (0–130) vs 320 (280–360) nmol Ca2+/mg protein p=0.004). Complexes I, II and IV were lowered after 2 hours of reperfusion in the RIR-37°C group (p<0.05), and complexes II and IV activities remained altered 24 hours after reperfusion, compared to Sham-37°C (p=0.009 and p=0.02 respectively). In the RIR-34°C group, complexes I, II and IV activities were preserved 2 hours after reperfusion but complex I activity decreased 24 hours after reperfusion. We found significant difference between complexes II and IV activities between IRI-34°C and RIR-37°C. Conclusion Mild hypothermia (34°C) during RIR significantly protected renal mitochondrial respiration and mitochondrial stress, associated with a preserved renal function after 2 hours of reperfusion and an improved renal function 24 hours after reperfusion compared to normothermic mice (37°C).

scholarly journals Bone Marrow–Derived Mononuclear Cell Therapy Accelerates Renal Ischemia-Reperfusion Injury Recovery by Modulating Inflammatory, Antioxidant and Apoptotic Related Molecules

2017 ◽  
Vol 41 (5) ◽  
pp. 1736-1752 ◽  
Author(s):  
Felipe Mateus Ornellas ◽  
Débora Santos Ornellas ◽  
Sabrina Vargas Martini ◽  
Raquel Carvalho Castiglione ◽  
Grasiella Maria Ventura ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Renal Function ◽  
Biological Markers ◽  
Mononuclear Cells ◽  
Cellular Therapy ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Proliferation Index ◽  
Anti Inflammatory

Background/Aims: We investigated the regenerative capacity of intravenous administration of bone marrow–derived mononuclear cells (BMMCs) in a rat model of bilateral renal ischemia/reperfusion (IR) injury and the involvement of inflammatory anti-inflammatory and other biological markers in this process. Methods: Rats were subjected to 1h bilateral renal pedicle clamping. BMMCs were injected i.v 1h after reperfusion and tracked by 99mTc and GFP+ BMMCs. Twenty-four hours after reperfusion, renal function and histological changes were evaluated. The mRNA (real time PCR) and protein (ELISA and immuno-staining) expression of biological markers were analyzed. Results: Renal function and structure improved after infusion of BMMCs in the IR group (IR-C). Labeled BMMCs were found in the kidneys after therapy. The expression of inflammatory and biological markers (TLR-2, TRL-4, RAGE, IL-17, HMGB-1, KIM-1) were reduced and the expression of anti-inflammatory and antioxidant markers (IL-10, Nrf2, and HO-1) were increased in IR-C animals compared with IR untreated animals (IR-S). The apoptotic index diminished and the proliferation index increased in IR-C compared with IR-S. Conclusion: The results contribute to our understanding of the role of different biological players in morphofunctional renal improvement and cytoprotection in a post-ischemic reperfusion kidney injury model subjected to cellular therapy.

scholarly journals High-Fat Diet Increased Oxidative Stress and Mitochondrial Dysfunction Induced by Renal Ischemia-Reperfusion Injury in Rat

2021 ◽  
Vol 12 ◽  
Author(s):  
Priyanka N. Prem ◽  
Gino A. Kurian
Keyword(s):  
Oxidative Stress ◽  
Renal Function ◽  
Mitochondrial Dysfunction ◽  
High Fat Diet ◽  
Ischemia Reperfusion ◽  
Protein Translation ◽  
Renal Ischemia ◽  
High Fat ◽  
Dietary Regimen ◽  
The Impact

Renal ischemia-reperfusion (IR) injury is one of the major causes of acute kidney injury influenced by the ischemic duration and the presence of comorbidities. Studies have reported that high-fat diet consumption can induce renal lipotoxicity and metabolic dyshomeostasis that can compromise the vital functions of kidney. This study aimed to evaluate the impact of a high-fat diet in the recovery of renal tissue from IR and explored the cellular pathology. In this study, 24 male Wistar rats were divided into two groups: normal diet (ND; n = 12) and high-fat diet (HD; n = 12), which were further subdivided into sham and IR groups at the end of the dietary regimen. The high-fat diet was introduced in 4-week-old rats and continued for 16 weeks. IR was induced by bilateral clamping of the renal peduncle for 45 min, followed by 24 h of reperfusion. Blood chemistry, estimated glomerular filtration rate (eGFR), mitochondrial function, and oxidative stress analysis were carried out to study the pathological changes. The rats fed with HD showed a decreased eGFR and elevated plasma creatinine, thereby compromised kidney function. Subcellular level changes in HD rats are deceased mitochondrial copy number, low PGC-1α gene expression, and declined electron transport chain (ETC) enzymes and adenosine triphosphate (ATP) level. Upon IR induction, HD rats exhibited severely impaired renal function (eGFR-0.09 ml/min) and elevated injury markers compared with ND rats. A histological analysis displayed increased tubular necrosis and cast formation in HD-IR in comparison to ND-IR. The oxidative stress and mitochondrial dysfunction were more prominent in HD-IR. In vitro protein translation assessment revealed impaired translational capacity in HD-IR mitochondria, which suggests mitochondrial changes with diet that may adversely affect the outcome of IR injury. High-fat diet consumption alters the normal renal function by modifying the cellular mitochondria. The renal changes compromise the ability of the kidney to recover from ischemia during reperfusion.

O2 metabolites cause reperfusion injury after short but not prolonged renal ischemia

1987 ◽  
Vol 253 (4) ◽  
pp. F685-F691 ◽  
Author(s):  
S. L. Linas ◽  
D. Whittenburg ◽  
J. E. Repine
Keyword(s):  
Renal Function ◽  
Reperfusion Injury ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Cellular Events ◽  
Perfusion Flow ◽  
Biochemical Assessment ◽  
Perfusion Flow Rate

Toxic O2 metabolites have been postulated to contribute to renal ischemia-reperfusion injury, but their biochemical assessment and contribution as a function of the duration of ischemia is unclear. To address this issue we measured renal function and renal cortical glutathione levels following 20, 30, or 45 min of ischemia in situ and then 60 min of reperfusion by the isolated kidney technique. Increasing durations of ischemia were associated with progressive decreases in perfusion flow rate, glomerular filtration rate, tubular Na reabsorption, and renal cortical glutathione following reperfusion. However, reperfusion following simultaneous addition of the permeable O2 metabolite scavenger dimethylthiourea (DMTU; but not urea) prevented glutathione consumption and attenuated reperfusion-induced injury after 20 and 30 min of ischemia. In contrast, reperfusion with DMTU prevented glutathione consumption but did not improve renal function after 45 min of ischemia. Similarly, reperfusion with dimethyl sulfoxide also attenuated renal injury after 20 and 30 min, but not after 45 min of ischemia. Thus reperfusion of kidneys made ischemic for 20 or 30 min is associated with decreases in tissue glutathione and renal function that were both inhibitable by addition of O2 metabolite scavengers during reperfusion. In contrast, addition of O2 metabolite scavengers during reperfusion of kidneys previously made ischemic for 45 min prevented decreases in glutathione but did not improve renal function. We conclude that O2 metabolites formed during reperfusion contribute to functional impairment in kidneys made ischemic for short durations up to 30 min) but that after prolonged ischemia (greater than 30 min) injury is primarily mediated by non-O2 metabolite-dependent cellular events.

Role of xanthine oxidase in ischemia/reperfusion injury

1990 ◽  
Vol 258 (3) ◽  
pp. F711-F716 ◽  
Author(s):  
S. L. Linas ◽  
D. Whittenburg ◽  
J. E. Repine
Keyword(s):  
Renal Function ◽  
Xanthine Oxidase ◽  
Ischemia Reperfusion ◽  
Physiological Role ◽  
Renal Ischemia ◽  
Total Enzyme Activity ◽  
Type D ◽  
Total Type ◽  
Oxygen Metabolites

Oxygen metabolites formed during reperfusion of ischemic kidneys prevent recovery of renal function after short periods of renal ischemia. Xanthine oxidase has been proposed as a source of toxic oxygen metabolites during reperfusion of ischemic kidneys. To determine whether the enzyme is converted from the non-oxygen metabolite-producing dehydrogenase (type D) to the oxygen metabolite-producing oxidase (type O), we measured type D and type O (total, reversible, and irreversible) xanthine oxidase in renal cortical homogenates after 30 min of ischemia in vivo and 60 min of reperfusion by the isolated perfused kidney technique. Total enzyme activity (type D plus type O) was not altered by ischemia or reperfusion. Compared with nonischemic conditions, ischemia increased total type O (53 +/- 5 vs. 21 +/- 3%, P less than 0.01) and reversible type O (15.4 +/- 1.5 vs. 2.1 +/- 1.4 U/g) xanthine oxidase activities. Reperfusion further increased total type O (82 +/- 3%) and reversible type O (27.7 +/- 3.3 U/g, both P less than 0.01 vs. nonischemic perfusions) xanthine oxidase activities. To determine the physiological role of xanthine oxidase in renal ischemia, we depleted rats of xanthine oxidase by feeding tungsten. After 4 wk of tungsten, renal xanthine oxidase levels were reduced by greater than 90% and renal function was markedly improved during reperfusion.(ABSTRACT TRUNCATED AT 250 WORDS)

A3 adenosine receptor knockout mice are protected against ischemia- and myoglobinuria-induced renal failure

2003 ◽  
Vol 284 (2) ◽  
pp. F267-F273 ◽  
Author(s):  
H. Thomas Lee ◽  
Ayuko Ota-Setlik ◽  
Hua Xu ◽  
Vivette D. D'Agati ◽  
Marlene A. Jacobson ◽  
...  
Keyword(s):  
Renal Failure ◽  
Renal Function ◽  
Knockout Mice ◽  
Adenosine Receptor ◽  
Renal Injury ◽  
Ischemia Reperfusion ◽  
Renal Ischemia ◽  
Renal Protection ◽  
A3 Adenosine Receptor ◽  
Renal Histology

A3 adenosine receptor (AR) activation and inhibition worsen and improve, respectively, renal function after ischemia-reperfusion (I/R) injury in rats. We sought to further characterize the role of A3 ARs in modulating renal function after either I/R or myoglobinuric renal injury. A3 knockout mice had significantly lower plasma creatinines compared with C57 controls 24 h after I/R or myoglobinuric renal injury. C57 control mice pretreated with the A3 AR antagonist [3-ethyl-5-benzyl-2-methyl-4-phenylethynyl-6-phenyl-1,4-(±)-dihydropyridine-3,5 dicarboxylate] or agonist [0.125 mg/kg N 6-(3-iodobenzyl)- N-methyl-5′-carbamoyladenosine (IB-MECA)] demonstrated improved or worsened renal function, respectively, after I/R or myoglobinuric renal injury. Higher doses of IB-MECA were lethal in C57 mice subjected to renal ischemia. H1 but not H2 histamine receptor antagonist prevented death in mice pretreated with IB-MECA before renal ischemia. Improvement in renal function was associated with significantly improved renal histology. In conclusion, preischemic A3 AR activation (0.125 mg/kg IB-MECA) exacerbated renal I/R injury in mice. Mice lacking A3 ARs or blocking A3 ARs in wild-type mice resulted in significant renal protection from ischemic or myoglobinuric renal failure.

Trehalose attenuates renal ischemia-reperfusion injury by enhancing autophagy and inhibiting oxidative stress and inflammation

2020 ◽  
Vol 318 (4) ◽  
pp. F994-F1005
Author(s):  
Suwen Liu ◽  
Yunwen Yang ◽  
Huiping Gao ◽  
Ning Zhou ◽  
Peipei Wang ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Renal Function ◽  
Renal Injury ◽  
Ischemia Reperfusion ◽  
Kidney Injury ◽  
Renal Ischemia ◽  
Renal Histology ◽  
Hypoxia Reoxygenation

Renal ischemia-reperfusion (IR) injury is one of the most common acute kidney injuries, but there is still a lack of effective treatment in the clinical setting. Trehalose (Tre), a natural disaccharide, has been demonstrated to protect against oxidative stress, inflammation, and apoptosis. However, whether it could protect against IR-induced renal injury needs to be investigated. In an in vivo experiment, C57BL/6J mice were pretreated with or without Tre (2 g/kg) through a daily single intraperitoneal injection from 3 days before renal IR surgery. Renal function, apoptosis, oxidative stress, and inflammation were analyzed to evaluate kidney injury. In an in vitro experiment, mouse proximal tubular cells were treated with or without Tre under a hypoxia/reoxygenation condition. Western blot analysis, autophagy flux detection, and apoptosis assay were performed to evaluate the level of autophagy and antiapoptotic effect of Tre. The in vivo results showed that the renal damage induced by IR was ameliorated by Tre treatment, as renal histology and renal function were improved and the enhanced protein levels of kidney injury molecule-1 and neutrophil gelatinase-associated lipocalin were blocked. Moreover, autophagy was activated by Tre pretreatment along with inhibition of the IR injury-induced apoptosis, oxidative stress, and inflammation. The in vitro results showed that Tre treatment activated autophagy and protected against hypoxia/reoxygenation-induced tubular cell apoptosis and oxidative stress. Our results demonstrated that Tre protects against IR-induced renal injury, possibly by enhancing autophagy and blocking oxidative stress, inflammation, and apoptosis, suggesting its potential use for the clinical treatment of renal IR injury.

scholarly journals The effect of the antioxidant drug U-74389G on urea levels during ischemia reperfusion injury in rats

2017 ◽  
Vol 11 ◽  
Author(s):  
Constantinos Tsompos ◽  
Constantinos Panoulis ◽  
Konstantinos Toutouzas ◽  
Aggeliki Triantafyllou ◽  
George Zografos ◽  
...  
Keyword(s):  
Experimental Study ◽  
Renal Function ◽  
Reperfusion Injury ◽  
Rat Model ◽  
Ischemia Reperfusion Injury ◽  
Ischemia Reperfusion ◽  
Serum Levels ◽  
Renal Ischemia

This experimental study examined the effect of the antioxidant drug U-74389G, on a rat model and particularly in a renal ischemia - reperfusion protocol. The effects of that molecule were studied biochemically using blood mean urea levels. Forty rats of mean weight 231.875 g were used in the study. Urea levels were measured at 60 min of reperfusion (groups A and C) and at 120 min of reperfusion (groups B and D). The drug U-74389G was administered only in groups C and D. U-74389G administration significantly decreased the predicted urea levels by 11.35%+2.73% (P=0.0001). Reperfusion time non-significantly increased the predicted urea levels by 2.26%+3.29% (P=0.4103). However, U-74389G administration and reperfusion time together significantly decreased the predicted urea levels by 6.31%+1.70% (P=0.0005). U-74389G administration whether it interacted or not with reperfusion time has significant decreasing effect on the urea serum levels, reflecting a respective renal function augmentation.

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